Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
 2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maturation-activated protein-serine/threonine kinases were investigated in the high-speed supernatant fractions from sea-star oocytes harvested at the time of germinal vesicle breakdown. One of the major stimulated protein kinases able to phosphorylate acetyl-CoA carboxylase in these extracts was found to co-purify with a 44 kDa myelin basic protein kinase (p44mpk) that is activated with a similar time course during oocyte maturation. Purified sea-star oocyte p44mpk phosphorylated acetyl-CoA carboxylase (purified from rat liver) predominantly on serine and to a small extent on threonine. Furthermore, the phosphorylation of acetyl-CoA carboxylase occurred principally on a tryptic phosphopeptide which displayed electrophoretic and chromatographic properties very similar to those of the peptide that has previously been shown to undergo increased phosphorylation in response to insulin in rat adipocytes [Brownsey & Denton (1982) Biochem. J. 202, 77-86]. The acetyl-CoA carboxylase was phosphorylated at a similar rate and to a similar extent by casein kinase II, which was also purified from maturing sea-star oocytes. Although casein kinase II was also activated approximately 3-fold near the time of nuclear envelope breakdown, it was responsible for only a minor component of the total enhanced acetyl-CoA carboxylase kinase activity measured in the soluble extracts from maturing oocytes. Acetyl-CoA carboxylase was a relatively poor substrate for the major S6 peptide kinase activity that was also stimulated during resumption of meiosis in the oocytes. The properties of the p44mpk are reminiscent of those of a microtubule-associated protein 2 (MAP-2) kinase that is activated in response to insulin and other mitogens in mammalian cells [Ray & Sturgill (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 3753-3757; Hoshi, Nishida & Sakai (1988) J. Biol. Chem. 263, 5396-5401]. It is intriguing that several of the mammalian protein kinases that are acutely activated after mitogenic prompting of quiescent mouse fibroblasts (i.e. G0 to G1 transition), such as MAP-2 kinase, casein kinase II and S6 kinase II, have counterparts that are activated during M-phase in maturing sea star oocytes.
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PMID:Identification of a major maturation-activated acetyl-CoA carboxylase kinase in sea star oocytes as p44mpk. 167 14

A protein kinase, termed microtubule-associated protein (MAP) kinase, which phosphorylates microtubule-associated protein 2 (MAP-2) in vitro and is stimulated 1.5-3-fold in extracts from insulin-treated 3T3-L1 cells has been identified (Ray, L.B., and Sturgill, T.W. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 1502-1506). Here, we describe chromatographic properties of MAP kinase and provide biochemical characterization of the partially purified enzyme. Isolation of the enzyme is facilitated by its unusually high affinity for hydrophobic interaction chromatography matrices. The molecular weight of the partially purified enzyme was determined to be 35,000 by gel filtration chromatography and 37,000 by glycerol gradient centrifugation. MAP kinase activity of chromatographic fractions correlated precisely with the presence of a 40-kDa phosphoprotein detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. MAP kinase has a Km of 7 microM for ATP and does not utilize GTP. Acetyl-CoA carboxylase, ATP citrate-lyase, casein, histones, phosvitin, protamine, and ribosomal protein S6 were all poor substrates relative to MAP-2. The enzyme is inhibited by fluoride and beta-glycerol phosphate but not by heparin. These properties of MAP kinase distinguish it from protein kinases previously described in the literature.
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PMID:Characterization of insulin-stimulated microtubule-associated protein kinase. Rapid isolation and stabilization of a novel serine/threonine kinase from 3T3-L1 cells. 284 41

We have investigated the signalling pathways involved in the stimulation of glycogen and fatty acid synthesis by insulin in rat fat cells using wortmannin, an inhibitor of phosphatidylinositol 3-kinase, and rapamycin, which blocks activation of p70 ribosomal S6 protein kinase (p70S6K). Insulin produced a decrease in the activity of glycogen synthase kinase-3 which is likely to be important in the observed stimulation of glycogen synthase. Both of these actions were found to be sensitive to inhibition by wortmannin. Activation of three processes is involved in the stimulation of fatty acid synthesis from glucose by insulin, namely glucose uptake, acetyl-CoA carboxylase and pyruvate dehydrogenase. Whereas wortmannin largely abolished the effects of insulin on glucose utilization and acetyl-CoA carboxylase activity, it was without effect on the stimulation of pyruvate dehydrogenase. Although epidermal growth factor stimulated mitogen-activated protein kinase to a greater extent than insulin, it was unable to mimic the effect of insulin on glycogen synthase, glycogen synthase kinase-3, glucose utilization, acetyl-CoA carboxylase or pyruvate dehydrogenase. Rapamycin also failed to have any appreciable effect on stimulation of these parameters by insulin, although it did block the effect of insulin on p70S6K. We conclude that the activity of phosphatidylinositol 3-kinase is required for the effects of insulin on glycogen synthesis, glucose uptake and acetyl-Co-AN carboxylase, but is not involved in signalling to pyruvate dehydrogenase. Activation of mitogen-activated protein kinase or p70S6K, however, does not appear to be sufficient to bring about the stimulation of fatty acid or glycogen synthesis. Altogether is seems likely that at least four distinct signalling pathways are involved in the effects of insulin on rat fat cells.
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PMID:Multiple signalling pathways involved in the stimulation of fatty acid and glycogen synthesis by insulin in rat epididymal fat cells. 748 1

The discovery of the mitogen-activated protein (MAP) kinase family of protein kinases has sparked off an intensive effort to elucidate their role in the regulation of many cellular processes. These protein kinases were originally identified based on their rapid activation by insulin. In this review we concentrate on examining the evidence for and against a role for the MAP kinases Erk-1 and Erk-2 in mediating the effects of insulin. While there is good evidence in favour of a direct role for MAP kinase in the growth-promoting effects of insulin and the regulation of Glut-1 and c-fos expression, and AP-1 transcriptional complex activity, this is by no means conclusive. MAP kinase may also play a role in the control of mRNA translation by insulin. On the other hand, the evidence suggests that MAP kinase is not sufficient for the acute regulation of glucose transport (Glut-4 translocation), glycogen synthesis, acetyl-CoA carboxylase or pyruvate dehydrogenase activity. The findings suggest that insulin may utilise at least three distinct signalling pathways which do not involve MAP kinase.
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PMID:Does mitogen-activated-protein kinase have a role in insulin action? The cases for and against. 786 19

Acetyl-CoA carboxylase (ACC) activity in the liver varies markedly as a function of the nutritional state and is subject to complex regulation involving variable enzyme content, enzyme specific activity due to variable phosphorylation, and zonation within the hepatic lobule. A 5'-AMP-activated protein kinase (AMPK) has been identified as the major regulatory kinase active on ACC. Employing dual-digitonin pulse perfusion, the effect of varying nutrition on periportal and perivenous zonation of ACC and AMPK activity within the liver has been characterized. During the transition from fasting to refeeding with high-carbohydrate chow, total ACC activity is increased 11- to 17-fold. This induction of total ACC activity is accounted for by a 4.5- to 6-fold increase in the content of the two major ACC isoforms and by a 2.5-to 3-fold increase in enzyme specific activity (units per mg ACC). Despite a small perivenous preponderance of ACC protein, a gradient of activity to the periportal side, due to this increase in specific activity, is observed in fasted rats and during early refeeding. After 24-48 h of refeeding, maximal induction of both ACC protein and specific activity is observed with obliteration of this total activity gradient. 5'-AMP-activated protein kinase activity is maximal in the fasted rat and is zonated to the perivenous side. During refeeding, this activity is rapidly markedly diminished with abolition of this gradient, correlating inversely with the activation of ACC over a narrow range of kinase activity. Activities of casein kinase II, myelin basic protein kinase(s), and ribosomal S6 kinase(s) show no zonation. These data suggest that the zonal activity of the 5'-AMP-activated protein kinase is responsible, in part, for the intrahepatic gradient in ACC activity and that the regulation of this kinase is responsible for the variations in ACC-specific activity that occur during varying nutrition.
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PMID:Hepatic 5'-AMP-activated protein kinase: zonal distribution and relationship to acetyl-CoA carboxylase activity in varying nutritional states. 790 5

Incubation of isolated hepatocytes with glutamine or proline or in hypotonic media is known to activate glycogen synthase and acetyl-CoA carboxylase as a result of cell swelling. We report here that the same experimental conditions caused an activation of phosphatidylinositol 3-kinase and p70 ribosomal protein S6 kinase (p70 S6 kinase) but did not modify the activity of p42 mitogen-activated protein kinase. In addition, rapamycin, an inhibitor of p70 S6 kinase activation, prevented the amino acid- and hypotonicity-induced activation of p70 S6 kinase but did not block the activation of glycogen synthase and acetyl-CoA carboxylase, thus ruling out p70 S6 kinase as a necessary component in the activation pathway. By contrast, wortmannin or LY294002, inhibitors of phosphatidylinositol 3-kinase, completely blocked the activation of phosphatidylinositol 3-kinase and p70 S6 kinase and partly blocked the activation of glycogen synthase and acetyl-CoA carboxylase. Therefore, phosphatidylinositol 3-kinase might be a component of the signaling pathway that is triggered by cell swelling and is responsible, at least in part, for the activation of glycogen synthase and acetyl-CoA carboxylase. Incubation of hepatocytes with 0.1 microM epidermal growth factor doubled the activity of p42 mitogen-activated protein kinase without activating glycogen synthase.
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PMID:Protein kinase signaling pathway triggered by cell swelling and involved in the activation of glycogen synthase and acetyl-CoA carboxylase in isolated rat hepatocytes. 866 1

The metabolic effects of insulin are initiated by the binding of insulin to the extracellular domain of the insulin receptor within the plasma membrane of muscle and adipose and liver cells. The subsequent activation of the intracellular tyrosine protein kinase activity of the receptor leads to autophosphorylation of the receptor as well as phosphorylation of a number of intracellular proteins. This gives rise to the activation of Ras and phosphatidylinositol 3-kinase and hence to the activation of a number of serine/threanine protein kinases. Many of these kinases appear to be arranged in cascades, including a cascade that results in the activation of mitogen-activated protein kinase and another that may result in the activation of protein kinase B, leading to the inhibition of glycogen synthase kinase-3 and the activation of the 70 kiloDalton ribosomal S6 protein kinase (p70 S6 kinase). We have explored the role of these early events in the the stimulation of glycogen, fatty acid, and protein synthesis by insulin in rat epididymal fat cells. Comparisons have been made between the metabolic effects of insulin and those of epidermal growth factor, since these 2 agents have contrasting effects on p70 S6 kinase and mitogen-activated protein kinase. The effects of wortmannin (which inhibits phosphatidylinositol 3-kinase), and rapamycin (which blocks the activation of p70 S6 kinase) have also been studied. These and other studies indicate that the mitogen-activated protein kinase cascade is probably not important in the acute metabolic effects of insulin, but may have a role in the regulation of gene transcription and hence the more long-term effects of insulin. The short-term metabolic effects of insulin appear to involve at least 3 distinct signaling pathways: (1) those leading to increases in glucose transport and the activation of glycogen synthase, acetyl-CoA carboxylase, eukaryotic initiation factor-2B, and phosphodiesterase, which may involve phosphatidylinositol 3-kinase and protein kinase B; (2) those leading to some of the effects of insulin on protein synthesis (formation of eukaryotic initiation factor-4F complex, S6 phosphorylation, and activation of eukaryotic elongation factor-2), which may involve phosphatidylinositol 3-kinase and p70 S6 kinase; and finally, (3) that leading to the activation of pyruvate dehydrogenase, which is unique in apparently not requiring activation of phosphatidylinositol 3-kinase.
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PMID:Multiple signaling pathways involved in the metabolic effects of insulin. 929 55

Biochemical, genetic, and animal studies in recent years have established a critical role for the adipokine Acrp30/adiponectin in controlling whole-body metabolism, particularly by enhancing insulin sensitivity in muscle and liver, and by increasing fatty acid oxidation in muscle. We describe a widely expressed and highly conserved family of adiponectin paralogs designated as C1q/tumor necrosis factor-alpha-related proteins (CTRPs) 1-7. In the present study, we focus on mCTRP2, the mouse paralog most similar to adiponectin. At nanomolar concentrations, bacterially produced mCTRP2 rapidly induced phosphorylation of AMP-activated protein kinase, acetyl-CoA carboxylase, and mitogen-activated protein kinase in C2C12 myotubes, which resulted in increased glycogen accumulation and fatty acid oxidation. The discovery of a family of adiponectin paralogs has implications for understanding the control of energy homeostasis and could provide new targets for pharmacologic intervention in metabolic diseases such as diabetes and obesity.
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PMID:A family of Acrp30/adiponectin structural and functional paralogs. 1523 94

The molecular signaling mechanisms by which insulin leads to increased glucose transport and metabolism and gene expression are not completely elucidated. We have characterized the nature of insulin signaling defects in skeletal muscle from Type 2 diabetic patients. Insulin receptor substrate (IRS-1) phosphorylation, phosphatidylinositol (PI) 3-kinase activity, and glucose transport activity are impaired as a consequence of functional defects, whereas insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase (MAPK) phosphorylation, and glycogen synthase activity are normal. Using biotinylated photoaffinity labeling, we have shown that reduced cell surface GLUT4 levels can explain glucose transport defects in skeletal muscle from Type 2 diabetic patients under insulin-stimulated conditions. Current work is focused on mechanisms behind insulin-dependent and insulin-independent regulation of glucose uptake. We have recently determined the independent effects of insulin and hypoxia/AICAR exposure on glucose transport and cell surface GLUT4 content in skeletal muscle from nondiabetic and Type 2 diabetic subjects. Hypoxia and AICAR increase glucose transport via an insulin-independent mechanism involving activation of 5'-AMP-activated kinase (AMPK). AMPK signaling is intact, because 5-aminoimidazole-4-carboxamide 1-beta-D-ribonucleoside (AICAR) increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation to a similar extent in Type 2 diabetic and nondiabetic subjects. However, AICAR responses on glucose uptake were impaired. Our studies highlight important AMPK-dependent and independent pathways in the regulation of GLUT4 and glucose transport activity in insulin resistant skeletal muscle. Understanding signaling mechanisms to downstream metabolic responses may provide valuable clues to a future therapy for Type 2 diabetes.
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PMID:Sending the signal: molecular mechanisms regulating glucose uptake. 1523 28

The MAP kinase pathway inhibitor U0126 caused phosphorylation and activation of AMP-activated protein kinase (AMPK) and increased phosphorylation of its downstream target acetyl-CoA carboxylase, in HEK293 cells. This effect only occurred in cells expressing the upstream kinase, LKB1. Of two other widely used MAP kinase pathway inhibitors not closely related in structure to U0126, PD98059 also activated AMPK but PD184352 did not. U0126 and PD98059, but not PD184352, also increased the cellular ADP:ATP and AMP:ATP ratios, accounting for their ability to activate AMPK. These results suggest the need for caution in interpreting experiments conducted using U0126 and PD98059.
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PMID:PD98059 and U0126 activate AMP-activated protein kinase by increasing the cellular AMP:ATP ratio and not via inhibition of the MAP kinase pathway. 1562 Jul 19


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